Pd-catalyzed Peptide C-H Bond Modification Based On Peptide Backbone As Directing Groups

Peptide drugs often have high target targeting and good biological activity.Chemical modification of peptides can often improve their protease stability and cell penetration,and improve their pharmacokinetic properties and druggability.In recent years,carbon-hydrogen bond activation strategies have been applied in the chemical modification of peptides.In this thesis,the research focuses on the alkenylation modification of specific sites in peptides with different targeting groups catalyzed by palladium.It is mainly divided into the following two parts:1.The olefination of thiazole-containing peptides via palladium-catalyzedδ-C（sp2）–H olefination of phenylalanine,tryptophan,and tyrosine residues has been developed.This strategy utilizes thiazole motifs as internal directing groups and provides access to thiazole-containing peptide macrocycles with bioactivities.This strategy has good compatibility with olefin substrates and polypeptide substrates,and can be used to realize the splicing of short peptides with amino acids and biomolecules.Fuether,21-25 membered cyclic peptide was successfully synthesized by this method and partially synthesized cyclic peptide molecules exhibit cytotoxicity against glioma U87MG and He La cells.2.A series of linear peptide and cyclic peptide precursor molecules containing phenylalanine and tryptophan were synthesized.Through peptide backbone orientation,the olefination modification of phenylalanine/tryptophan side chainδ-C（sp²）-H was realized,and macrocyclic peptides of various sizes and sequences were successfully synthesised.Through the trifluoromethanesulfonyl orientation at the nitrogen end of tryptophan,the olefination modification of tryptophan indole ring C₄ is realized,which complements the olefination modification strategy of tryptophan indole ring C₂.The olefination modification of phosphoramide directed to the ortho position of the benzyl group of the benzyl phosphoramide compound was studied.This strategy utilizes the phosphoramide as the directing groups to realize the olefination modification of the ortho position of the benzyl group,and successfully realizes the synthesis of macrocyclic peptides.